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Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression

Virchows Archiv volume 462, pages 437–443 (2013)Cite this article

An Erratum to this article was published on 01 June 2013

Abstract

Multidrug resistance protein 4 (MRP4) is a transmembrane transport protein found in many cell types and is involved in substrate-specific transport of endogenous and exogenous substrates. Recently, it has shown to be expressed in prostate cancer cell lines and to be among the most commonly upregulated transcripts in prostate cancer, although a comprehensive expression analysis is lacking so far. We aimed to investigate its expression by immunohistochemistry in a larger cohort of neoplastic and nonneoplastic prostate tissues (n = 441) and to correlate its expression with clinicopathological parameters including PSA-free survival times and molecular correlates of androgen signaling (androgen receptor (AR), prostate-specific antigen (PSA), and forkhead box A (FoxA)). MRP4 is widely expressed in benign and neoplastic prostate epithelia, but its expression gradually decreases during tumor progression towards castrate-resistant disease. Concordantly, it correlated with conventional prognosticators of disease progression and—within the group of androgen-dependent tumors—with AR and FoxA expression. Moreover, lower levels of MRP4 expression were associated with shorter PSA relapse-free survival times in the androgen-dependent group. In benign tissues, we found zone-dependent differences of MRP4 expression, with the highest levels in the peripheral and central zones. Although MRP4 is known to be regulated in prostate cancer, this study is the first to demonstrate a gradual downregulation of MRP4 protein during malignant tumor progression and a prognostic value of this loss of expression.

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Conflict of interest

Any financial or conflicting interests in the publication of this article are disclosed by the authors.

Author information

Affiliations

  1. Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland

    Matteo Montani

  2. Division of Urology, University Hospital Zurich, Zurich, Switzerland

    Thomas Herrmanns, Michael Müntener & Tullio Sulser

  3. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland

    Peter Wild

  4. Institute of Pathology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany

    Glen Kristiansen

Authors
  1. Matteo Montani
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  2. Thomas Herrmanns
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  3. Michael Müntener
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  4. Peter Wild
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  5. Tullio Sulser
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  6. Glen Kristiansen
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Corresponding author

Correspondence to Glen Kristiansen.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00428-013-1429-x.

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ESM 1
figure 4

Different immunohistochemical staining intensities for membranous MRP4 expression in non-neoplastic tissue: a) hyperplastic glands from the transitional zone with weak membranous positivity (Score 1), b) strong continuous positivity (Score 3) in glands from the ventral zone, c) glands from the peripheral zone with strong but variable positivity (Score 2), d) atrophic glands from the peripheral zone with virtually no membranous positivity (Score 0). (JPEG 116 kb)

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ESM 2
figure 5

Mean expression levels of MRP4, epithelial and stromal AR, FoxA and PSA expression in different categories, such as normal tissue from the peripheral zone, primary carcinomas and castrate resistant and metastasizing disease, respectively. (JPEG 587 kb)

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Montani, M., Herrmanns, T., Müntener, M. et al. Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression. Virchows Arch 462, 437–443 (2013). https://doi.org/10.1007/s00428-013-1390-8

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  • DOI: https://doi.org/10.1007/s00428-013-1390-8

Keywords

  • Prostate cancer
  • MRP4
  • Androgen receptor
  • FoxA
  • Immunohistochemistry